The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement.

Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (>5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without. The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD. Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause of death in NAFLD/NASH patients.

The hepatoprotective and hypolipidemic effects of Spirulina (Arthrospira platensis) supplementation in a Cretan population with non-alcoholic fatty liver disease: a prospective pilot study.

BACKGROUND: A pilot study was conducted to determine the effects of Spirulina (Arthrospira platensis) on Cretan patients with non-alcoholic fatty liver disease (NAFLD). Spirulina is a filamentous cyanobacterium taken as a dietary supplement. METHODS: Fifteen adult Cretan outpatients (13 men), median age 48 (range: 29-62) years, with NAFLD were orally supplemented with 6 g of Spirulina (Greek production) per day for six months. Anthropometric characteristics (height, weight, waist circumference), systolic and diastolic blood pressure, complete blood count, biochemical assessments, homeostasis model assessment of insulin resistance (HOMA-IR) index, health-related quality of life and abdominal sonographic findings were recorded and measured, before and after Spirulina supplementation. RESULTS: At the end of the 6-month intervention period, the mean levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, triglycerides, low-density lipoprotein-cholesterol, total cholesterol, and the ratio of total cholesterol to high-density lipoprotein cholesterol were significantly decreased: 38.5%, 37.5%, 26.7%, 24.8%, 9.6%, 9.1%, and 13.5% respectively, whereas the mean levels of high-density lipoprotein-cholesterol and hemoglobin were significantly increased: 4.2% and 4.1% respectively. Spirulina supplementation resulted also in a significant reduction in weight and HOMA-IR index (8.1% and 19.6% respectively) and a significant improvement in health-related quality of life scale. No changes in sonographic findings were observed. CONCLUSION: Spirulina supplementation at a high dosage of 6 g daily in NAFLD patients has strong and multiple beneficial metabolic effects and improves their health-related quality of life.

The hypolipidaemic effects of Spirulina (Arthrospira platensis) supplementation in a Cretan population: a prospective study.

BACKGROUND: Spirulina (Arthrospira platensis) is a filamentous cyanobacterium used as a food supplement. The objective of the study was to determine the lipid-lowering effects of Spirulina in Cretan Greek dyslipidaemic patients, and to document its effectiveness as a possible alternative treatment for dyslipidaemia. Fifty-two adultCretan outpatients (32 men, 20 women), median age 47 (range, 37-61) years, with recently diagnosed dyslipidaemia, consumed orally 1 g Spirulina (Greek production) per day for 12 weeks. The full lipid profile was measured in fasting blood samples at the beginning and end of the study period. Anthropometric measurements including systolic and diastolic blood pressure, height, weight and body mass index were also recorded. RESULTS: At the end of the 3-month intervention period the mean levels of triglycerides, low density lipoprotein-cholesterol, total cholesterol, non-high density lipoprotein-cholesterol levels, and the ratio of total cholesterol to high-density lipoproteincholesterol were significantly decreased: 16.3% (P < 0.0001), 10.1% (P < 0.0001), 8.9% (P < 0.0001), 10.8% (P < 0.0001) and 11.5% (P = 0.0006) respectively, whereas the mean high-density lipoprotein-cholesterol levels were not significantly increased (3.5%). Blood pressure, weight and body mass index remained almost unchanged. CONCLUSIONS: Spirulina supplementation at a dose of 1 g daily has powerful hypolipidaemic effects, especially on the triglyceride concentration in dyslipidaemic Cretan outpatients.

Microalbuminuria: a neglected cardiovascular risk factor in non-diabetic individuals?

Microalbuminuria (MA), excessive albumin excretion in the urine, is defined in different ways. MA is more prevalent among patients with diabetes mellitus (DM) and/or hypertension and correlates with adverse renal and cardiovascular (CV) outcomes. Several cross-sectional and prospective studies have demonstrated a positive association between MA and CV outcomes in the general population but also specific populations such as patients with previous MI and hypertensives. The relationship between MA and hypertension is of particular importance. Increased urine albumin excretion (UAE) has been associated with left ventricular hypertrophy (LVH), subclinical markers of atherosclerosis and vascular dysfunction. Metabolic syndrome (MetS), insulin resistance (IR), inflammatory markers, lipid parameters and measures of obesity also correlate with increased UAE. Accumulating evidence suggests that a UAE value lower than the "traditionally" considered microalbuminuric threshold is associated with increased CV risk. The revision of MA definition according to the levels which confer increased CV risk in the general population should probably be considered. Further prospective studies with uniform methods of urine collection and UAE measurement as well as consistent threshold values and units may provide additional information regarding MA (or low-grade albuminuria) as a predictor of CV outcomes.

Prevalence of metabolic syndrome according to different definitions in a hypertensive population.

AIMS: The metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Several definitions of MetS have been proposed. The aim of the present study was to estimate and compare the prevalence of MetS according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), American Heart Association-National Heart Lung and Blood Institute (AHA-NHLBI), International Diabetes Federation (IDF) and the more recent Joint Interim Statement (JIS) definitions in patients attending a hypertension clinic. METHODS: The records of patients referred to the hypertension clinic at the University Hospital (Heraklion, Crete) from January 2001 to June 2009 were screened retrospectively. A total 384 patients (146 men) were included in the study. RESULTS: The prevalence of MetS according to the IDF and JIS definitions was significantly higher compared with that of the NCEP ATP III in both genders (IDF: P = .009 and P = .002, JIS: P = .002 and P = 0.001 for men and women, respectively); this was the case for the AHA-NHLBI definition only among women (P = .03). All MetS components differed significantly (P from < .0001 to .02) between patients with and without MetS for all definitions. CONCLUSIONS: The prevalence of MetS varies considerably depending on the definition used in a hypertensive population in a Mediterranean country. These differences will influence risk assessment.

The role of serum magnesium and calcium on the association between adiponectin levels and all-cause mortality in end-stage renal disease patients.

BACKGROUND: Adiponectin (ADPN) is the most abundant adipocyte-specific cytokine that plays an important role in energy homeostasis by regulating lipid and glucose metabolism. Studies of the impact of ADPN on clinical outcomes have yielded contradictory results so far. Here, we examined the association of ADPN with serum magnesium (s-Mg) and calcium (s-Ca) levels and explored the possibility whether these two factors could modify the relationship between ADPN and all-cause mortality in patients with end-stage renal disease. METHODOLOGY/PRINCIPAL FINDINGS: After baseline assessment, 47 hemodialysis and 27 peritoneal dialysis patients were followed- up for a median period of 50 months. S-Mg and s-Ca levels emerged as positive and negative predictors of ADPN levels, respectively. During the follow-up period 18 deaths occurred. There was a significant 4% increased risk for all-cause mortality for each 1-µg/ml increment of ADPN (crude HR, 1.04; 95% CI, 1.01-1.07), even after adjustment for s-Mg and s-Ca levels, dialysis mode, age, albumin and C-reactive protein. Cox analysis stratified by s-Mg levels (below and above the median value of 2.45 mg/dl) and s-Ca levels (below and above the median value of 9.3 mg/dl), revealed ADPN as an independent predictor of total mortality only in the low s-Mg and high s-Ca groups. Furthermore, low s-Mg and high s-Ca levels were independently associated with malnutrition, inflammation, arterial stiffening and risk of death. CONCLUSIONS/SIGNIFICANCE: The predictive value of ADPN in all-cause mortality in end-stage renal disease patients appears to be critically dependent on s-Mg and s-Ca levels. Conversely, s-Mg and s-Ca may impact on clinical outcomes by directly modifying the ADPN's bioactivity.

Lipid lowering drugs and gallstones: a therapeutic option?

Cholelithiasis is a common disease worldwide. The majority of gallstones can occur when the bile is supersaturated with cholesterol. Dyslipidaemia, obesity, insulin resistance are associated with an increased risk for cholesterol gallstone formation as well as with vascular risk. Statins and ezetimibe are used to treat dyslipidaemia and appear to have some effect on bile composition and cholesterol gallstone formation. Statin (e.g. pravastatin, simvastatin, fluvastatin and lovastatin) monotherapy or combined with ursodeoxycholic acid (UDCA) have shown reductions in bile cholesterol saturation, preventing gallstone formation and even dissolving pre-existing stones. However, this effect was not consistently reported in all studies. Statin use has also been associated with a reduced risk for cholecystectomy in 2 large epidemiological studies. Ezetimibe was shown to have a beneficial action against cholelithiasis in animal studies but data in humans - although promising - are very limited. The effect of these drugs on gallstone disease warrants further investigation in large human trials. We also consider the links between cholelithiasis, vascular risk and the use of lipid lowering drugs.

Liver enzymes: potential cardiovascular risk markers?

Several cross-sectional studies have reported a relationship between elevated serum activity of liver enzymes [e.g. alanine aminotransferase (ALT) and gamma-glutamyltransferase (γGT)] and metabolic syndrome (MetS) and/or diabetes mellitus (DM). Raised serum activity of liver enzymes independently predicted the future development of MetS and DM as well as cardiovascular (CV) events and/or total/CV mortality in prospective studies. However, this association was not consistently demonstrated and it appears to be independent of alcohol intake. Even though these associations can be partly attributed to non-alcoholic fatty liver disease (NAFLD) and insulin resistance, there may be additional underlying mechanisms that contribute to the increased CV risk (e.g. inflammation and oxidative stress). The association of γGT with atherosclerotic plaque is of particular importance.

Ezetimibe; more than a low density lipoprotein cholesterol lowering drug? An update after 4 years.

Ezetimibe (EZE), a selective inhibitor of intestinal cholesterol absorption, is mostly used in combination with statins across various patient populations. Besides its low-density lipoprotein cholesterol (LDL-C) lowering, EZE exerts different effects on several other variables. In an earlier review, we discussed the effects of EZE on lipid parameters other than LDL-C [e.g. C-reactive protein (CRP) levels, insulin sensitivity and endothelial function]. In the present review, we consider recent evidence regarding these topics as well as data reporting novel EZE actions. EZE may protect from cholelithiasis and non-alcoholic fatty liver disease (NAFLD) and appears as an effective lipid-lowering treatment option for human-immunodeficiency virus (HIV)-positive patients, transplant recipients and children with familial hypercholesterolaemia (FH). Studies with EZE that raised concern about its effects on atherosclerosis are also discussed. The potential clinical benefit of these actions with respect to vascular events and overall mortality remains to be established in appropriately designed trials.

The estrogenic burden on vascular risk in male-to-female transsexuals.

Transsexualism refers to individuals that identify themselves as members of the opposite gender and who strive to acquire the physical appearance and psychosocial role compatible with that gender. Gender reassignment therapy is applied through hormonal treatment ± surgical intervention in addition to psychological support. Hormone treatment for male-to-female transsexuals includes estrogen supplementation ± suppression of androgen secretion or action. Sex hormones are important determinants of the metabolic profile. The impact on cardiovascular disease appears to be gender-related but overall evidence remains conflicting. Gender reassignment therapy has been associated with elevated triglyceride concentrations, often accompanied by an increase in high density lipoprotein levels, reduced circulating homocysteine (Hcy), uric acid and creatinine levels as well as an adverse effect on glycemic control. Markers of inflammation, oxidative stress and endothelial function are also affected in various ways, while alterations in hemostatic and fibrinolytic factors favor thrombosis (arterial and/or venous). Male-to-female transsexuals may be adversely affected by both estrogen administration and androgen deprivation, as reported in prostate cancer. Therefore, vascular risk factor screening and potential intervention may be required prior to and during gender reassignment therapy (both hormone and surgical).

Delays incurred during acute myocardial infarction: a comparative study of rural and urban populations in Greece.

INTRODUCTION: Treatment delay during myocardial infarction may be due to a number of factors, such as age, sex, socioeconomic status and interpretation of symptoms. However, whether residence plays a role has not been fully investigated and, if known, could provide information that will help target specific populations. This study investigated whether urban and rural residents in Greece differ in the time required to seek and receive medical assistance during acute myocardial infarction, according to their characteristics and the determinants of their delay. METHODS: This was an observational study (with a structured interview) conducted in one academic and one regional hospital on the island of Crete, Greece, consisting of 348 patients with confirmed myocardial infarction. RESULTS: Patients from rural and urban areas did not differ in the decision time before seeking medical assistance (180 min vs 240 min, p=0.058). Those living in rural areas experienced a longer delay in reaching hospital once they sought assistance (50 min vs 20 min, p<0.0001). The total median delay time (4.25 hours for rural and 4.75 hours for urban patients, p=0.9) was positively affected by female sex and negatively affected by a patient's belief that symptoms were serious, and that they were heart-related. CONCLUSIONS: Strategies should be developed to reduce the treatment delay during myocardial infarction for residents of both urban and rural areas, especially for women. Patients interpreting symptoms as being serious and originating from the heart are important for a shorter delay. A better health system is needed in rural Greece in order to deal more effectively with medical emergencies such as myocardial infarction.

Atorvastatin for diabetic macular edema in patients with diabetes mellitus and elevated serum cholesterol.

BACKGROUND AND OBJECTIVE: To determine the efficacy of atorvastatin in reducing hard exudates and diabetic macular edema. PATIENTS AND METHODS: An uncontrolled clinical case series included 18 eyes with diabetic maculopathy and an elevated baseline lipid profile. All patients were treated with atorvastatin. Ophthalmologic evaluation, including fundus photography and fluorescein angiography, was performed at presentation and repeated at 3, 6, and 12 months. Hard exudates, hemorrhages, and fluorescein leakage at 12 months were evaluated and compared with baseline findings. RESULTS: Eighteen subjects with diabetic maculopathy received atorvastatin, and a significant decrease in total cholesterol and low-density lipoprotein cholesterol was seen (P < .05). Hard exudates and fluorescein leakage were decreased. No evidence of an association between change in hemorrhage status and treatment was found. CONCLUSION: Oral atorvastatin therapy in patients with diabetes mellitus and dyslipidemia seems to reduce the severity of hard exudates and fluorescein leakage in diabetic maculopathy and could be useful as an adjuvant therapy in the management of diabetic macular edema.

Comparison of four definitions of the metabolic syndrome in a Greek (Mediterranean) population.

BACKGROUND: There is a need to evaluate the prevalence of metabolic syndrome (MetS) diagnosed by the new Joint Interim Societies (JIS) MetS definition. The JIS definition was compared with three previous definitions to assess their ability to predict cardiovascular disease (CVD) risk. METHODS: A cross-sectional analysis of a representative sample of Greek adults (n = 9669) was performed to estimate the prevalence of MetS and CVD using the JIS vs. the three older definitions of MetS: the National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATP-III), the International Diabetes Federation (IDF) and the American Heart Association/National Heart Lung and Blood Institute (AHA/NHLBI) definitions. RESULTS: The age-adjusted MetS prevalence was 45.7%, 43.4%, 24.5% and 26.3% (ANOVA p < 0.001) with the JIS, IDF, NCEP and AHA/NHLBI definitions. The prevalence of CVD was 11.4% in the whole study population and 17.6%, 18.3%, 23.3%, 22.6% and in subjects with MetS according to the JIS, IDF, NCEP and AHA/NHLBI definitions (ANOVA p < 0.001). The prevalence of CVD was only 10.4% (i.e., lower than in the whole study population) in subjects with MetS according to the JIS but not according to the NCEP-ATP-III and AHA/NHLBI definitions (p < 0.001 vs. subjects with MetS as defined by NCEP-ATP-III or AHA/NHLBI). CONCLUSIONS: When diagnosed according to the new JIS definition, the prevalence of MetS was high in a Greek Mediterranean cohort (nearly half of the adult population). The NCEP-ATP-III and AHA/NHLBI definitions were more predictive of CVD risk than the new JIS definition. These findings, though limited by the cross sectional analysis, may have implications regarding the choice of the definition to diagnose MetS.

Kidney function and estimated vascular risk in patients with primary dyslipidemia.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased vascular risk. Some studies suggested that considering markers of CKD might improve the predictive accuracy of the Framingham risk equation. AIM: To evaluate the links between kidney function and risk stratification in patients with primary dyslipidemia. METHODS: Dyslipidemic patients (n = 156; 83 men) who were non-smokers, did not have diabetes mellitus or evident vascular disease and were not on lipid-lowering or antihypertensive agents were recruited. Creatinine clearance (CrCl) was estimated using the Cockcroft-Gault equation. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) equation. We estimated vascular risk using the Framingham equation. RESULTS: In both men and women, there was a significant negative correlation between estimated Framingham risk and both eGFR and CrCl (p < 0.001 for all correlations). When men were divided according to creatinine tertiles, there were no significant differences in any parameter between groups. When men were divided according to either eGFR or CrCl tertiles, all estimated Framingham risks significantly increased as renal function declined (p<0.001 for all trends). When women were divided according to creatinine tertiles, all estimated Framingham risks except for stroke significantly increased as creatinine levels increased. When women were divided according to either eGFR or CrCl tertiles, all estimated Framingham risks significantly increased as renal function declined. CONCLUSIONS: Estimated vascular risk increases as renal function declines. The possibility that incorporating kidney function in the Framingham equation will improve risk stratification requires further evaluation.

Acute rhabdomyolysis caused by Spirulina (Arthrospira platensis).

Rhabdomyolysis is a potentially life-threatening disorder that occurs as a primary disease or as a complication of a broad spectrum of other diseases. We report the first case of acute rhabdomyolysis after ingestion of Spirulina (Arthrospira platensis), a plantonic blue-green alga, as a dietary supplement.

Effects of 12 months treatment with L-selenomethionine on serum anti-TPO Levels in Patients with Hashimoto's thyroiditis.

OBJECTIVE: We studied the effects of selenium (Se) treatment on serum anti-thyroid peroxidase (TPO) levels in Greek patients with Hashimoto's thyroiditis (HT). DESIGN: We prospectively studied 80 women with HT, median age 37 (range 24-52) years, for 1 year. All patients received 200 microg Se in the form of l-selenomethionine orally for 6 months. At the end of the 6-month period, 40 patients continued taking 200 microg Se (Group A) and 40 patients stopped (Group B). Serum thyrotropin (TSH), free triiodothyronine (FT(3)), free thyroxine (FT(4)), anti-TPO, and anti-thyroglobulin (Tg) levels were measured at baseline and at the end of each 3-month period. MAIN OUTCOME: There was a significant reduction of serum anti-TPO levels during the first 6 months (by 5.6% and 9.9% at 3 and 6 months, respectively). An overall reduction of 21% (p < 0.0001) compared with the basal values was noted in Group A. In Group B, serum anti-TPO levels were increased by 4.8% (p < 0.0001) during the second 6-month period. CONCLUSIONS: Our study showed that in HT patients 6 months of Se treatment caused a significant decrease in serum anti-TPO levels, which was more profound in the second trimester. The extension of Se supplementation for 6 more months resulted in an additional 8% decrease, while the cessation caused a 4.8% increase, in the anti-TPO concentrations.

Fibrinogen, lipoprotein (a), albumin and bilirubin (F-L-A-B) levels and cardiovascular risk calculated using the Framingham equation.

OBJECTIVES: To determine the correlation between cardiovascular risk calculated using the Framingham equation and the circulating levels of 4 'emerging'predictors of vascular events: fibrinogen (Fib), lipoprotein (a) (Lp(a)), albumin (Alb) and bilirubin (Bil) (F-L-A-B). PATIENTS AND METHODS: A retrospective survey was carried out using patients referred to a specialist university-based clinic. A total of 376 patients with primary dyslipidaemia (209 men), without overt vascular disease, had their cardiovascular risk estimated using the Framingham equation. RESULTS: Among the men, smokers (n=45) were significantly younger (p =0.014) than non-smokers (n=164). Smokers when compared with non-smokers had significantly higher median Fib levels (3.84 (1.15-5.87) vs. 3.08 (1.44-5.47) g/l; p<0.0001) and lower median Bil levels (8 (3-17) vs. 10 (1-28) micromol/l; p=0.016). When non-smoker men without clinically evident vascular disease were considered, there was a significant positive Fib and negative Alb correlation with calculated risk, whether the family history was considered or not. Moreover in smokers, the only significant correlation was a negative one between Bil and cardiovascular disease risk. Lp(a) correlated with risk for stroke in women non-smokers whether the family history was considered or not, while Alb correlated with risk for stroke in women non-smokers without family history. CONCLUSION: Fib, Lp(a), Alb and Bil (F-L-A-B) may be predictors of vascular events in high-risk populations. Prospective studies should evaluate whether the F-L-A-B markers are useful in the assessment of cardiovascular risk load. Such an advantage would make treatment more cost effective by improving patient targeting. The F-L-A-B markers could eventually become targets for new drugs.

Identifying and attaining LDL-C goals: mission accomplished? Next target: new therapeutic options to raise HDL-C levels.

Currently, low density lipoprotein cholesterol (LDL-C) levels are the main, if not the only, lipid target in the effort to reduce cardiovascular disease (CVD) morbidity and mortality. Several primary and secondary CVD prevention trials with statins shaped current guidelines and provided detailed targets across a range of CVD risk categories. These targets can be attained using effective statins or combination therapy. However, the net benefit in CVD risk reduction may be improved if we address other lipid risk factors. High density lipoprotein cholesterol (HDL-C) emerges from epidemiological studies as the most promising target. This review links the increase in HDL-C levels with clinical benefit from "old" (e.g. sustained release niacin) and new treatment options. Synthetically produced recombined apolipoprotein A-I Milano administered intravenously seems to have a marked effect in reducing the atheroma burden. The anti-cholesterol ester transfer protein (CETP) vaccine (CETi-1) produces auto-antibodies against CETP thus increasing the cholesterol ester content in HDL particles. CETP inhibitors (e.g. JTT-705 and torcetrapib) seem to be the most promising regimen to increase HDL-C levels. Torcetrapib (already in phase IIIa studies) can substantially increase HDL-C levels (up to 106%), alone or in combination with atorvastatin. HDL-C strategies, in combination with effective statins, are a new drug target aimed at a further reduction in CVD morbidity and mortality compared with statin monotherapy.